A new potent inhibitor of converting enzyme: (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid(SA446).

(2R, 4R)-2-(2-Hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid (SA446) is a novel potent converting enzyme inhibitor having a sulfhydryl group in the molecule. SA446 inhibited the activity of semi-purified rabbit lung converting enzyme (IC50 = 6 nM). The contractile response of isolated guinea pig ileum to angiotensin I (AI) was markedly inhibited by SA446 (IC50 = 28 nM). On the other hand, SA446 augmented the contraction to bradykinin (BK) (AC50 = 0.7 nM), but did not affect the contraction caused by angiotensin II (AII), acetylcholine and histamine. These in vitro potencies of SA446 were 4 to 5 times larger than those of captopril. SA446 inhibited the pressor response to AI in rats (ID50 = 0.06 mg/kg, i.v., 0.48 mg/kg, p.o.) and dogs (ID50 = 0.01 mg/kg, i.v.). SA446 augmented the depressor response to BK (AD50 = 0.009 mg/kg, i.v.), but did not affect the pressor responses to AII and norepinephrine in rats. These in vivo activities of SA446 in dogs were more potent than those of captopril, but the reverse was seen in rats. Oral administration of SA446 had a hypotensive effect on two-kidney, one-clip renal hypertensive rats and spontaneously hypertensive rats, at doses over 3 and 10 mg/kg, respectively. However, the blood pressure of normotensive and DOCA-salt hypertensive rats was not affected by SA446, in doses up to 100 mg/kg. These results indicate that oral SA446 is a potent active inhibitor of converting enzyme and may be classed as an antihypertensive agent.